Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan; Department of Pediatrics, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan.
J Allergy Clin Immunol. 2022 Jan;149(1):252-261.e6. doi: 10.1016/j.jaci.2021.05.018. Epub 2021 Jun 24.
Patients with Mendelian susceptibility to mycobacterial disease (MSMD) experience recurrent and/or persistent infectious diseases associated with poorly virulent mycobacteria. Multifocal osteomyelitis is among the representative manifestations of MSMD. The frequency of multifocal osteomyelitis is especially high in patients with MSMD etiologies that impair cellular response to IFN-γ, such as IFN-γR1, IFN-γR2, or STAT1 deficiency.
This study sought to characterize the mechanism underlying multifocal osteomyelitis in MSMD.
GM colonies prepared from bone marrow mononuclear cells from patients with autosomal dominant (AD) IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 gain of function (GOF) and from healthy controls were differentiated into osteoclasts in the presence or absence of IFN-γ. The inhibitory effect of IFN-γ on osteoclastogenesis was investigated by quantitative PCR, immunoblotting, tartrate-resistant acid phosphatase staining, and pit formation assays.
Increased osteoclast numbers were identified by examining the histopathology of osteomyelitis in patients with AD IFN-γR1 deficiency or AD STAT1 deficiency. In the presence of receptor activator of nuclear factor kappa-B ligand and M-CSF, GM colonies from patients with AD IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-γ concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-γR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF.
Osteoclast differentiation is increased in AD IFN-γR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-γ, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis.
孟德尔易感性分枝杆菌病（MSMD）患者会反复出现和/或持续性感染与低毒力分枝杆菌相关的疾病。多灶性骨髓炎是 MSMD 的代表性表现之一。IFN-γR1、IFN-γR2 或 STAT1 缺陷等细胞对 IFN-γ反应受损的 MSMD 病因患者，多灶性骨髓炎的频率尤其高。
本研究旨在阐明 MSMD 中多灶性骨髓炎的发病机制。
从常染色体显性（AD）IFN-γR1 缺陷、AD STAT1 缺陷或 STAT1 功能获得（GOF）患者和健康对照者的骨髓单核细胞 GM 集落中制备 GM 集落，并在有无 IFN-γ的情况下分化为破骨细胞。通过定量 PCR、免疫印迹、抗酒石酸酸性磷酸酶染色和陷窝形成测定来研究 IFN-γ对破骨细胞生成的抑制作用。
通过检查 AD IFN-γR1 缺陷或 AD STAT1 缺陷患者骨髓炎的组织病理学，发现破骨细胞数量增加。在核因子 kappa-B 配体受体激活剂和 M-CSF 的存在下，AD IFN-γR1 缺陷、AD STAT1 缺陷或 STAT1 GOF 患者的 GM 集落分化为破骨细胞，类似于健康志愿者的 GM 集落。AD IFN-γR1 缺陷或 AD STAT1 缺陷患者的 GM 集落中，IFN-γ浓度依赖性的破骨细胞形成抑制受损，而 STAT1 GOF 患者的 GM 集落中增强。
由于对 IFN-γ的反应受损，AD IFN-γR1 缺陷和 AD STAT1 缺陷中破骨细胞分化增加，导致破骨细胞过度增殖，进而推断感染灶中骨吸收增加，这可能是多灶性骨髓炎的基础。
